Identification of key genes in great saphenous varicose veins: A bioinformatics analysis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WU Nan ,  XIE Chunyang

Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150023, P. R. China;

Corresponding author：

XIE Chunyang, Email: xcy83629@sina.com

Keywords：

great saphenous varicosis vein; bioinformatics analysis; core genes

DOI：

10.7507/1007-9424.202406002

Video：

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Objective To identify the core genes involved in the great saphenous varicose veins (GSVVs) through bioinformatics methods. Methods The transcriptional data of GSVVs tissues and normal great saphenous vein tissues (control tissues) were downloaded from the gene expression omnibus (GEO) database. The single sample gene set enrichment analysis (ssGSEA) was used to calculate Hallmark score. The Weighted Gene Co-expression Network Analysis (WGCNA) combined with machine learning algorithms was used to screen the key genes relevant GSVVs. The protein-protein interaction (PPI) analysis was performed using the String database, and the receiver operating characteristic (ROC) curve was used to reflect the discrimination ability of the target genes for GSVVs. Results Compared with the control tissues, there were 548 up-regulated genes and 706 down-regulated genes in the GSVVs tissues, the Hallmark points of KRAS signaling and apical junction were down-regulated, while which of peroxisomes, coagulation, reactive oxygen species pathways, etc. were up-regulated in the GSVVs tissues. A total of 639 differentially expressed genes related to GSVVs were obtained and 165 interaction relation between proteins encoded by 372 genes, and the top 10 genes with the highest betweenness values, ADAM10, APP, NCBP2, SP1, ASB6, ADCY4, HP, UBE2C, QSOX1, and CXCL1, were located at the center of the interaction relation. And the core genes were mainly related to copper ion homeostasis, neutrophil degranulation G protein coupled receptor signaling, response to oxidative stress, and regulation of amide metabolism processes. The SP1 and QSOX1 are both Hub genes. The expressions of the SP1 and QSOX1 in the GSVVs tissues were significantly up-regulated as compared with the control tissues. The area under the ROC curve of SP1 and QSOX1 in distinguishing GSVVs tissues from normal tissues was 0.972 and 1.000, respectively. Conclusions SP1 and QSOX1 are core genes in the occurrence and development of GSVVs. Regulation of SP1 and QSOX1 genes is expected to achieve precise treatment of GSVVs.

1.	Béliard S, Ferreira D, Thomas H, et al. High physical activity volume is associated with an increase in the calibre of the lower limb veins without impact on functional discomfort: the VARISPORT study. Eur J Vasc Endovasc Surg, 2023, 66(6): 856-863.
2.	Zeng M, Teng B, Zhao Y, et al. Effectiveness of iliac vein stenting combined with endovenous laser treatment of recurrent varicose veins associated with iliac vein compression. Quant Imaging Med Surg, 2023, 13(9): 5986-5995.
3.	Tepelenis K, Papathanakos G, Kitsouli A, et al. Prevalence and risk factors of phlebosclerosis in the great saphenous vein. Vascular, 2023, 10: 17085381231162134. doi: 10.1177/17085381231162134.
4.	Gao RD, Qian SY, Wang HH, et al. Strategies and challenges in treatment of varicose veins and venous insufficiency. World J Clin Cases, 2022, 10(18): 5946-5956.
5.	Lim CS, Davies AH. Pathogenesis of primary varicose veins. Br J Surg, 2009, 96(11): 1231-1242.
6.	Surendran S, S Ramegowda K, Suresh A, et al. Arterialization and anomalous vein wall remodeling in varicose veins is associated with upregulated FoxC2-Dll4 pathway. Lab Invest, 2016, 96(4): 399-408.
7.	Meissner MH, Gloviczki P, Bergan J, et al. Primary chronic venous disorders. J Vasc Surg, 2007, 46 Suppl S: 54S-67S. doi: 10.1016/j.jvs.2007.08.038.
8.	Lee JD, Lai CH, Yang WK, et al. Increased expression of hypoxia-inducible factor-1α and metallothionein in varicocele and varicose veins. Phlebology, 2012, 27(8): 409-415.
9.	Sprague AH, Khalil RA. Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol, 2009, 78(6): 539-552.
10.	Harbsmeier AN, Altintas I, Iversen K, et al. Biomarkers and the post-thrombotic syndrome: A systematic review of biomarkers associated with the occurrence of the post-thrombotic syndrome after lower extremity deep venous thrombosis. Phlebology, 2023, 38(9): 577-598.
11.	Chen YS, Lu MJ, Huang HS, et al. Mechanosensitive transient receptor potential vanilloid type 1 channels contribute to vascular remodeling of rat fistula veins. J Vasc Surg, 2010, 52(5): 1310-1320.
12.	Liu Y, Chen S, Wang Y, et al. The diagnostic and prognostic value of the immune checkpoint BGN in thymoma. Biochem Genet, 2024, 62(3): 1872-1894.
13.	Li H, Wang Y, Li G, et al. Integrative analysis of cuproptosis-associated genes for predicting immunotherapy response in single-cell and multi-cohort studies. J Gene Med, 2024, 26(1): e3600. doi: 10.1002/jgm.3600.
14.	Zhou Y, Zhou B, Pache L, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun, 2019, 10(1): 1523. doi: 10.1038/s41467-019-09234-6.
15.	Schmid-Schönbein GW, Takase S, Bergan JJ. New advances in the understanding of the pathophysiology of chronic venous insufficiency. Angiology, 2001, 52 Suppl 1: S27-S34. doi: 10.1177/0003319701052001S04.
16.	Ortega MA, Fraile-Martínez O, García-Montero C, et al. Understanding chronic venous disease: A critical overview of its pathophysiology and medical management. J Clin Med, 2021, 10(15): 3239. doi: 10.3390/jcm10153239.
17.	Milkiewicz M, Doyle JL, Fudalewski T, et al. HIF-1alpha and HIF-2alpha play a central role in stretch-induced but not shear-stress-induced angiogenesis in rat skeletal muscle. J Physiol, 2007, 583(Pt 2): 753-766.
18.	Lim CS, Kiriakidis S, Paleolog EM, et al. Increased activation of the hypoxia-inducible factor pathway in varicose veins. J Vasc Surg, 2012, 55(5): 1427-1439.
19.	Anwar MA, Shalhoub J, Vorkas PA, et al. In-vitro identification of distinctive metabolic signatures of intact varicose vein tissue via magic angle spinning nuclear magnetic resonance spectroscopy. Eur J Vasc Endovasc Surg, 2012, 44(4): 442-450.
20.	Anwar MA, Vorkas PA, Li J, et al. Prolonged mechanical circumferential stretch induces metabolic changes in rat inferior vena cava. Eur J Vasc Endovasc Surg, 2016, 52(4): 544-552.
21.	Xu X, Wang X, Chen Q, et al. Sp1 promotes tumour progression by remodelling the mitochondrial network in cervical cancer. J Transl Med, 2023, 21(1): 307. doi: 10.1186/s12967-023-04141-3.
22.	Obi S, Masuda H, Shizuno T, et al. Fluid shear stress induces differentiation of circulating phenotype endothelial progenitor cells. Am J Physiol Cell Physiol, 2012, 303(6): C595-C606. doi: 10.1152/ajpcell.00133.2012.
23.	Sohl M, Lanner F, Farnebo F. Sp1 mediate hypoxia induced ephrinB2 expression via a hypoxia-inducible factor independent mechanism. Biochem Biophys Res Commun, 2010, 391(1): 24-27.
24.	Ma Q, Yu M, Zhou B, et al. QSOX1 promotes mitochondrial apoptosis of hepatocellular carcinoma cells during anchorage-independent growth by inhibiting lipid synthesis. Biochem Biophys Res Commun, 2020, 532(2): 258-264.
25.	Woodside KJ, Hu M, Burke A, et al. Morphologic characteristics of varicose veins: possible role of metalloproteinases. J Vasc Surg, 2003, 38(1): 162-169.
26.	Raffetto JD, Khalil RA. Mechanisms of lower extremity vein dysfunction in chronic venous disease and implications in management of varicose veins. Vessel Plus, 2021, 5: 36. doi: 10.20517/2574-1209.2021.16.

1. Béliard S, Ferreira D, Thomas H, et al. High physical activity volume is associated with an increase in the calibre of the lower limb veins without impact on functional discomfort: the VARISPORT study. Eur J Vasc Endovasc Surg, 2023, 66(6): 856-863.
2. Zeng M, Teng B, Zhao Y, et al. Effectiveness of iliac vein stenting combined with endovenous laser treatment of recurrent varicose veins associated with iliac vein compression. Quant Imaging Med Surg, 2023, 13(9): 5986-5995.
3. Tepelenis K, Papathanakos G, Kitsouli A, et al. Prevalence and risk factors of phlebosclerosis in the great saphenous vein. Vascular, 2023, 10: 17085381231162134. doi: 10.1177/17085381231162134.
4. Gao RD, Qian SY, Wang HH, et al. Strategies and challenges in treatment of varicose veins and venous insufficiency. World J Clin Cases, 2022, 10(18): 5946-5956.
5. Lim CS, Davies AH. Pathogenesis of primary varicose veins. Br J Surg, 2009, 96(11): 1231-1242.
6. Surendran S, S Ramegowda K, Suresh A, et al. Arterialization and anomalous vein wall remodeling in varicose veins is associated with upregulated FoxC2-Dll4 pathway. Lab Invest, 2016, 96(4): 399-408.
7. Meissner MH, Gloviczki P, Bergan J, et al. Primary chronic venous disorders. J Vasc Surg, 2007, 46 Suppl S: 54S-67S. doi: 10.1016/j.jvs.2007.08.038.
8. Lee JD, Lai CH, Yang WK, et al. Increased expression of hypoxia-inducible factor-1α and metallothionein in varicocele and varicose veins. Phlebology, 2012, 27(8): 409-415.
9. Sprague AH, Khalil RA. Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol, 2009, 78(6): 539-552.
10. Harbsmeier AN, Altintas I, Iversen K, et al. Biomarkers and the post-thrombotic syndrome: A systematic review of biomarkers associated with the occurrence of the post-thrombotic syndrome after lower extremity deep venous thrombosis. Phlebology, 2023, 38(9): 577-598.
11. Chen YS, Lu MJ, Huang HS, et al. Mechanosensitive transient receptor potential vanilloid type 1 channels contribute to vascular remodeling of rat fistula veins. J Vasc Surg, 2010, 52(5): 1310-1320.
12. Liu Y, Chen S, Wang Y, et al. The diagnostic and prognostic value of the immune checkpoint BGN in thymoma. Biochem Genet, 2024, 62(3): 1872-1894.
13. Li H, Wang Y, Li G, et al. Integrative analysis of cuproptosis-associated genes for predicting immunotherapy response in single-cell and multi-cohort studies. J Gene Med, 2024, 26(1): e3600. doi: 10.1002/jgm.3600.
14. Zhou Y, Zhou B, Pache L, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun, 2019, 10(1): 1523. doi: 10.1038/s41467-019-09234-6.
15. Schmid-Schönbein GW, Takase S, Bergan JJ. New advances in the understanding of the pathophysiology of chronic venous insufficiency. Angiology, 2001, 52 Suppl 1: S27-S34. doi: 10.1177/0003319701052001S04.
16. Ortega MA, Fraile-Martínez O, García-Montero C, et al. Understanding chronic venous disease: A critical overview of its pathophysiology and medical management. J Clin Med, 2021, 10(15): 3239. doi: 10.3390/jcm10153239.
17. Milkiewicz M, Doyle JL, Fudalewski T, et al. HIF-1alpha and HIF-2alpha play a central role in stretch-induced but not shear-stress-induced angiogenesis in rat skeletal muscle. J Physiol, 2007, 583(Pt 2): 753-766.
18. Lim CS, Kiriakidis S, Paleolog EM, et al. Increased activation of the hypoxia-inducible factor pathway in varicose veins. J Vasc Surg, 2012, 55(5): 1427-1439.
19. Anwar MA, Shalhoub J, Vorkas PA, et al. In-vitro identification of distinctive metabolic signatures of intact varicose vein tissue via magic angle spinning nuclear magnetic resonance spectroscopy. Eur J Vasc Endovasc Surg, 2012, 44(4): 442-450.
20. Anwar MA, Vorkas PA, Li J, et al. Prolonged mechanical circumferential stretch induces metabolic changes in rat inferior vena cava. Eur J Vasc Endovasc Surg, 2016, 52(4): 544-552.
21. Xu X, Wang X, Chen Q, et al. Sp1 promotes tumour progression by remodelling the mitochondrial network in cervical cancer. J Transl Med, 2023, 21(1): 307. doi: 10.1186/s12967-023-04141-3.
22. Obi S, Masuda H, Shizuno T, et al. Fluid shear stress induces differentiation of circulating phenotype endothelial progenitor cells. Am J Physiol Cell Physiol, 2012, 303(6): C595-C606. doi: 10.1152/ajpcell.00133.2012.
23. Sohl M, Lanner F, Farnebo F. Sp1 mediate hypoxia induced ephrinB2 expression via a hypoxia-inducible factor independent mechanism. Biochem Biophys Res Commun, 2010, 391(1): 24-27.
24. Ma Q, Yu M, Zhou B, et al. QSOX1 promotes mitochondrial apoptosis of hepatocellular carcinoma cells during anchorage-independent growth by inhibiting lipid synthesis. Biochem Biophys Res Commun, 2020, 532(2): 258-264.
25. Woodside KJ, Hu M, Burke A, et al. Morphologic characteristics of varicose veins: possible role of metalloproteinases. J Vasc Surg, 2003, 38(1): 162-169.
26. Raffetto JD, Khalil RA. Mechanisms of lower extremity vein dysfunction in chronic venous disease and implications in management of varicose veins. Vessel Plus, 2021, 5: 36. doi: 10.20517/2574-1209.2021.16.

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Latest ArticlesIdentification of key genes in great saphenous varicose veins: A bioinformatics analysis

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